Browsing by Autor "Rafael Contreras Lopez"

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Demonstration of immunomodulatory properties for the human MuStem cell population, a promising candidate for cell therapy of muscular dystrophies
(Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, 2018) Judith Lorant; Marine Charrier; Rafael Contreras Lopez; Christophe Blanquart; Blandine Lieubeau; Cindy Schleder; Isabelle Leroux; Gaël Tejedor; Candice Babarit; Yann Péréon
Over the last eighteen years, the identification of stem cells in adult tissue opened new opportunities in cellbased\ntherapy strategy. However, allogeneic cell transplantation protocols are highly limited by graft rejection.\nTo overcome this issue, long-term immunosuppression (IS) are classically used, resulting in improved cell\nengraftment but also major adverse effects. Recently, many in vitro studies demonstrated pleiotropic\nimmunomodulatory properties for adult stem cells, especially mesenchymal ones that have been shown\nto modulate the behavior of many immune cells through paracrine secretion or direct contact. These features\ncould increase their ability to engraft in allogeneic recipient despite the lack of strong IS, thus\nimproving their therapeutic efficiency. In addition, delivery of cells with immune privilege behavior may be\nbeneficial in the context of degenerative disorders to limit chronic inflammation that characterizes tissues and\ninterfere with the repair process.\nIn the lab, we isolated muscle-derived stem cells (termed MuStem cells) from healthy dogs and\ndemonstrated that their systemic delivery in dystrophic dogs submitted to continuous IS lead to muscle\nregeneration and long-term clinical status stabilization. Interestingly, an IS restricted to the transplantation\nperiod was shown to be sufficient to sustain their transplantation benefits and to prevent host immunity\nresponse in allogeneic context, suggesting a possible immune privilege behaviour for the hMuStem\ncells. Recently, human MuStem cells were isolated and characterized as exhibiting in vitro/in vivo myogenic\npotential, positioning them as a promising candidate for muscle-dedicated regenerative medicine.\nThe aim of the present study is to explore the immunological-related features of hMuStem\ncells and more specifically the interaction with T-cell features and the complement system\nactivation, two key effectors of allograft rejection.
PPARβ/δ Priming Enhances the Anti-Apoptotic and Therapeutic Properties of Mesenchymal Stromal Cells in Myocardial Ischemia-Reperfusion Injury
(Research Square (United States), 2021) Charlotte Sarre; Rafael Contreras Lopez; Nitirut Nerpernpisooth; Christian Barrère; Sarah Bahraoui; Claudia Terraza; Gautier Téjédor; Anne Vincent; Patricia Luz‐Crawford; Kantapich Kongpol
Abstract Background: Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives: The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. Methods and results: Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H 2 0 2 . Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on co-cultured cardiomyocytes. When injected during reperfusion in an ex vivo heart model of myocardial infarction, PPARβ/δ-primed MSC at a dose of 3.75x10 5 MSC/heart provided the same cardioprotective efficiency than 7.5x10 5 naïve MSC, identified as the optimal dose in our model. These enhanced short-term cardioprotective effects were associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 hour of reperfusion. By contrast, inhibition of PPARβ/δ before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion: Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.